We have identified a number of nonallelic histone variants which are involved both in the replication of chromosomes and in the maintenance and repair of tissue-specific patterns of chromatin conformation, an important mechanism for preserving the normal patterns of gene expression in long-lived, nondividing cells of adult mammals. We have identified several distinct modes of expression of histone gene clusters in the mouse genome using several histone variant mutants discovered by us. We have found the expression of different histone variants changes at the time of commitment of cells to terminal differentiation and that histone variant ratios are useful indicators of spontaneous or induced rates of cell turnover or regeneration in adult tissues. We are using histone variant ratios as an assay for studying commitment to terminal differentiation, a likely common defect in cancer cells, as well as for the development of a safe clinical test for chronically increased rates of cell turnover which may be an important cause of premature aging and tumor promotion. (D)